Image directed lymph node sampling for lung cancer staging

http://deepblue.lib.umich.edu/bitstream/2027.42/117374/1/40644_2014_Article_102.pd

Uptake of minimally invasive surgery and stereotactic body radiation therapy for early stage non-small cell lung cancer in the USA

BACKGROUND: We aimed to assess the uptake of minimally invasive surgery (MIS) and stereotactic body radiation therapy (SBRT) among early stage (stage IA-IIB) non-small cell lung cancer (NSCLC) cases in the USA, and the rate of conversions from MIS to open surgery. MATERIALS AND METHODS: Data were obtained from the US National Cancer Database, a nationwide facility-based cancer registry capturing up to 70% of incident cancer cases in the USA. We included cases diagnosed with early stage (clinical stages IA-IIB) NSCLC between 2010 and 2014. In an ecological analysis, we assessed changes in treatment by year of diagnosis. Among surgically treated cases, we assessed the uptake of MIS and whether conversion to open surgery took place. For cases that received thoracic radiotherapy, we assessed the uptake of SBRT. RESULTS: Among 117 370 selected cases, radiotherapy use increased 3.4 percentage points between 2010 and 2014 (p<0.0001). Surgical treatments decreased 3.5 percentage points (p<0.0001). Rates of non-treatment remained stable (range: 10.0%-10.6% (p=0.4066)). Among surgically treated stage IA cases, uptake of MIS increased from 28.7% (95% CI 27.8% to 29.7%) in 2010 to 48.6% (95% CI 47.6% to 49

Role of C‐X‐C chemokines as regulators of angiogenesis in lung cancer

Lung cancer is the leading cause of malignancy‐related mortality in the U.S. and is predicted to increase over the remainder of this decade. Despite attempts to advance early diagnosis and use combination therapies, the clinical response of this cancer yields an overall 5‐year survival rate of less than 15%. Clearly, new strategies for therapy are indicated. Although carcinogenesis is complex, tumor growth beyond 1–2 mm3 is dependent on angiogenesis. One of the potential mechanisms that allows for tumorigenesis is dysregulation of the balance of angiogenic and angiostatic factors that favors net neovascularization within the primary tumor. Numerous studies have investigated the role of a variety of molecules in the regulation of angiogenesis. Recently, interleukin‐8 (IL‐8), a member of the C‐X‐C chemokine family, has been found to be an angiogenic factor. In contrast, platelet factor 4 (PF4), another C‐X‐C chemokine, has been shown to have angiostatic properties. It is interesting that the major structural difference between IL‐8 and PF4 is the presence of the NH2‐terminal ELR (Glu‐Leu‐Arg) motif that precedes the first cysteine amino acid residue of IL‐8 and is important in ligand/receptor interactions. We hypothesize that angiogenesis associated with tumorigenesis is dependent on members of the C‐X‐C chemokine family acting as either angiogenic or angiostatic factors. This paradigm predicts that the biological balance in the expression of these C‐X‐C chemokines dictates whether the neoplasm grows and develops metastatic potential or regresses. In this review we discuss our recent laboratory findings that support this contention and suggest that further elucidation of the biology of C‐X‐C chemokines in the context of neovascularization of nonsmall cell lung cancer will permit novel targeted therapy aimed specifically at attenuating tumor growth and metastasis. J. Leukoc. Biol. 57: 752–762; 1995.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141888/1/jlb0752.pd

CXC chemokines in angiogenesis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141036/1/jlb0001.pd

Treatment capacity required for full-scale implementation of lung cancer screening in the United States

BACKGROUND: Full-scale implementation of lung cancer screening in the United States will increase detection of early stages. This study was aimed at assessing the capacity required for treating those cancers. METHODS: A well-established microsimulation model was extended with treatment data from the National Cancer Database. We assessed how treatment demand would change when implementing lung cancer screening in 2018. Three policies were assessed: 1) annual screening of current smokers and former smokers who quit fewer than 15 years ago, aged 55 to 80 years, with a smoking history of at least 30 pack-years (US Preventive Services Task Force [USPSTF] recommendations); 2) annual screening of current smokers and former smokers who quit fewer than 15 years ago, aged 55 to 77 years, with a smoking history of at least 30 pack-years (Centers for Medicare and Medicaid Services [CMS] recommendations); and 3) annual screening of current smokers and former smokers who quit fewer than 10 years ago, aged 55 to 75 years, with a smoking history of at least 40 pack-years (the most cost-effective policy in Ontario [Ontario]). The base-case screening adherence was a constant 50%. Sensitivity analyses assessed other adherence levels, including a linear buildup to 50% between 2018 and 2027. RESULTS: The USPSTF policy would require 37.0% more lung cancer surgeries in 2015-2040 than no screening, 2.2% less radiotherapy, and 5.4% less chemotherapy; 5.7% more patients would require any therapy. The increase in surgical demand would be 96.1% in 2018, 46.0% in 2023, 38.3% in 2028, and 24.9% in 2040. Adherence strongly influenced results. By 2018, surgical demand would range from 52,619 (20% adherence) to 96,121 (80%). With a gradual buildup of adherence, the increase in surgical demand would be 9.6% in 2018, 38.3% in 2023, 42.0% in 2028, and 24.4% in 2040. Results for the CMS and Ontario policies were similar, although the changes in comparison with no screening were smaller. CONCLUSIONS: Full-scale implementation of lung cancer screening causes a major increase in surgical demand, with a peak within the first 5 years. A gradual buildup of adherence can spread this peak over time. Careful surgical capacity planning is essential for successfully implementing screening. Cancer 2019;125:2039-2048. © 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made

Lung CD8+ T cells in COPD have increased expression of bacterial TLRs

Abstract Background Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. Methods Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants. Results All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-γ and TNF-α by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD. Conclusions These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1.http://deepblue.lib.umich.edu/bitstream/2027.42/112427/1/12931_2012_Article_1320.pd

CXC chemokines mechanism of action in regulating tumor angiogenesis

The CXC chemokines have recently been identified as a family of molecules which can regulate angiogenesis. Members of this family which contain the amino acid motif Glu–Leu–Arg in their amino terminus (ELR + ) act as angiogenic factors, while ELR − members act as angiostatic molecules. The balance of these angiogenic versus angiostatic factors is critical in regulating homeostasis. As we detail in this review, there is increasing evidence from a variety of tumor model systems to suggest that the angiogenic members of this family and their receptors may be playing an important role in the neovascular pathology of solid tumors. In contrast, the angiostatic effects of the ELR − ; family members may provide novel therapeutic strategies for treating many tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41760/1/10456_2004_Article_176940.pd

Basal Gene Expression by Lung CD4+ T Cells in Chronic Obstructive Pulmonary Disease Identifies Independent Molecular Correlates of Airflow Obstruction and Emphysema Extent

Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also exists in some smokers with normal spirometry, and may contribute to development and progression of specific COPD phenotypes. Trial Registration ClinicalTrials.gov as NCT0028122

The Lynx X-Ray Observatory: Concept Study Overview and Status

Lynx, one of four strategic mission concepts under study for the 2020 Astrophysics Decadal Survey, will provide leaps in capability over previous and planned X-ray missions, and will provide synergistic observations in the 2030s to a multitude of space- and ground-based observatories across all wavelengths. Lynx will have orders of magnitude improvement in sensitivity, on-axis sub-arcsecond imaging with arcsecond angular resolution over a large field of view, and high-resolution spectroscopy for point-like and extended sources. The Lynx architecture enables a broad range of unique and compelling science, to be carried out mainly through a General Observer Program. This Program is envisioned to include detecting the very first supermassive black holes, revealing the high-energy drivers of galaxy and structure formation, characterizing the mechanisms that govern stellar activity - including effects on planet habitability, and exploring the highest redshift galaxy clusters. An overview and status of the Lynx concept are summarized

Pleural Dye Marking of Lung Nodules by Electromagnetic Navigation Bronchoscopy

IntroductionElectromagnetic navigation bronchoscopy (ENB)‐guided pleural dye marking is useful to localize small peripheral pulmonary nodules for sublobar resection.ObjectiveTo report findings on the use of ENB‐guided dye marking among participants in the NAVIGATE study.MethodsNAVIGATE is a prospective, multicentre, global and observational cohort study of ENB use in patients with lung lesions. The current subgroup report is a prespecified 1‐month interim analysis of ENB‐guided pleural dye marking in the NAVIGATE United States cohort.ResultsThe full United States cohort includes 1215 subjects from 29 sites (April 2015 to August 2016). Among those, 23 subjects (24 lesions) from seven sites underwent dye marking in preparation for surgical resection. ENB was conducted for dye marking alone in nine subjects while 14 underwent dye marking concurrent with lung lesion biopsy, lymph node biopsy and/or fiducial marker placement. The median nodule size was 10 mm (range 4‐22) and 83.3% were <20 mm in diameter. Most lesions (95.5%) were located in the peripheral third of the lung, at a median of 3.0 mm from the pleura. The median ENB‐specific procedure time was 11.5 minutes (range 4‐38). The median time from dye marking to resection was 0.5 hours (range 0.3‐24). Dye marking was adequate for surgical resection in 91.3%. Surgical biopsies were malignant in 75% (18/24).ConclusionIn this study, ENB‐guided dye marking to localize lung lesions for surgery was safe, accurate and versatile. More information is needed about surgical practice patterns and the utility of localization procedures.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151973/1/crj13077_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151973/2/crj13077.pd